tbuckley/cabot-search huggingface dataset:
Abstract 495: Discovery of BPI-221351, a potent, selective, orally available, and brain penetrating dual inhibitor of mutant IDH1/2
Authors: Hongling Shen, Xiaofeng Xu, Yabin Li, Xizhen Song, Jie Chen, Yunting Bi, Jing Guo, Tong Xu, Huijuan Zhang, Lijia Liu, Zhengyao Zou, Jialin Ren, Jun Tong, Xiaoyun Liu, Hongfei Rong, Teng Ma, Chao Wang, Xiangyong Liu, Hong Chen, Jiayu Zhao, Xuepeng Ju, Haibo Chen, Haidi Shen, Hong Lan, Lieming Ding, Jiabing Wang
Journal: Cancer Research (2023)

Abstract Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are critical enzymes of the tricarboxylic acid cycle, which convert isocitrate into α-ketoglutarate (α-KG). IDH1 or IDH2 mutations are observed in more than 80% of low- to mid-grade gliomas and in ~20% of acute myeloid leukemia (AML). Tumor-related IDH1/2 mutants acquire a novel function of using α-KG as a substrate to produce R-2-hydroxyglutarate (2-HG). 2-HG is an oncogenic metabolite, and reducing it by inhibiting mutant IDH1 or IDH2 has been shown to be an effective treatment approach. Although agents targeting IDH1 or IDH2 have been approved to treat IDH-mutant cancers, existing IDH1 inhibitors do not cross the blood-brain barrier, a feature needed for treating glioma. Furthermore, resistant mutations do occur, including cross-isoform mutations, which call for the development of dual IDH1/2 inhibitors with good brain penetration. However, IDH1/2 dual inhibitors are rarely discovered. Here we report the discovery of BPI-221351, a potent inhibitor of mutant IDH1 and mutant IDH2. BPI-221351 shows excellent inhibitory activities against both IDH1 and IDH2 enzymes, and potently suppresses 2-HG levels in tumor cells harboring IDH1 or IDH2 mutants. In an IDH-mutant xenograft model, BPI-221351 reduced 2-HG to baseline level up to 24 h after a single oral dose administration. In addition, BPI-221351 possesses excellent blood-brain-barrier penetration with a higher drug concentration in the brain than that in plasma. In conclusion, BPI-221351 exhibits strong activity towards both IDH1 and IDH2 mutants in vitro and in vivo with favorable pharmacological properties, presenting a new therapeutic opportunity for treating glioma and other relevant cancers. Citation Format: Hongling Shen, Xiaofeng Xu, Yabin Li, Xizhen Song, Jie Chen, Yunting Bi, Jing Guo, Tong Xu, Huijuan Zhang, Lijia Liu, Zhengyao Zou, Jialin Ren, Jun Tong, Xiaoyun Liu, Hongfei Rong, Teng Ma, Chao Wang, Xiangyong Liu, Hong Chen, Jiayu Zhao, Xuepeng Ju, Haibo Chen, Haidi Shen, Hong Lan, Lieming Ding, Jiabing Wang. Discovery of BPI-221351, a potent, selective, orally available, and brain penetrating dual inhibitor of mutant IDH1/2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 495.
Abstract 6755: The impact of renin-angiotensin system inhibitors on survival outcomes of pancreatic adenocarcinoma patients
Authors: Kuan-Yu Tseng, Cheng-Wei Chou
Journal: Cancer Research (2023)

Abstract Introduction Pancreatic adenocarcinoma (PDAC) is a highly aggressive malignancy with significant morbidity and mortality. RAS (renin-angiotensin system) inhibitors have been used for hypertension, and the potential role of using RAS inhibitors in pancreatic adenocarcinoma have been investigated in pre-clinical models by enhancing drug delivery and reducing hypoxia. However, the clinical benefit of RAS inhibitors in pancreatic cancer patients was still unclear. Methods We retrospectively investigated the impact of RAS inhibitors on survival outcomes of pancreatic adenocarcinoma patients in Taichung Veterans General Hospital between January 2014 and July 2021. Patients with histologically proven pancreatic adenocarcinoma were included in the study. Clinical feature with drugs exposure and survival outcome were analyzed. Results A total of 384 pancreatic cancer patients were analyzed. Among them, 70 patients had concurrent use of RAS inhibitors and 314 patients had no concurrent medication use. Among patients with RAS inhibitors use, the diagnosed age was significantly older (70.0 vs. 68.0, p = 0.023), and a higher proportion of hypertension (100.0% vs. 51.0%, p &amp;lt; 0.0001), chronic kidney disease (27.5% vs. 9.1%, p &amp;lt; 0.0001), and diabetes (64.3% vs 39.5%, p &amp;lt; 0.0001) than those without RAS inhibitors use. The 12-month progression-free survival were 22.9% and 13.7% in the RAS inhibitors and control group (p = 0.008), respectively. The Overall survival was not significantly different in the both groups (p = 0.356). In the multivariate analysis, the use of RAS inhibitors had a significantly better progression-free survival outcome (Hazard ratio = 0.025, CI:0.52-0.96). The advanced disease status, poor ECOG performance status and the elevated level of CA19-9 were correlated with poor progression-free survival. Conclusion In our study, although higher percentage of existed comorbidities in the RAS inhibitor group, we demonstrated that the use of RAS inhibitors among pancreatic cancer patients might provide a better progression-free survival outcome. Further prospective study and investigation are warranted. Citation Format: Kuan-Yu Tseng, Cheng-Wei Chou. The impact of renin-angiotensin system inhibitors on survival outcomes of pancreatic adenocarcinoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6755.
Abstract 123: Molecular mechanisms of RNA and DNA editing in leukemic transformation of hemopoietic stem and progenitor cells
Authors: Jane Marie Isquith, Jessica Pham, Thomas Whisenant, Larisa Balaian, Catriona Jamieson
Journal: Cancer Research (2023)

Abstract Dysregulation of inflammatory cytokine responsive APOBEC3 cytosine deaminases has been shown to be a contributing factor in cancer evolution, presenting as gene expression changes and inclusion of distinct C-to-T mutation patterns. However, the context specificity and mechanisms by which APOBEC3 enzymes promote cancer initiation and progression require further elucidation. Lentiviral overexpression of APOBEC3C and an editase deficient APOBEC3C mutant in healthy cord blood, bone marrow and MPN patient hematopoietic stem/progenitor cells (HSPCs) allows us to study the effects of innate immune deaminase dysregulation in the hematopoietic niche. We are focusing on the upregulation of APOBEC3C and adenosine deaminase acting on RNA1 (ADAR1), as we have previously shown them to be contemporaneously upregulated in the high-risk myelofibrosis (MF) stem cell population compared to normal aged bone marrow. We can compare these novel differential gene expression changes, RNA hyper-editing sites, and DNA mutation signatures induced by APOBEC3 mutagenesis to abnormalities seen in both hematopoietic malignancies and solid tumor cancers. Gene set enrichment analysis (GSEA) performed on this dataset has exposed numerous deregulated pathways brought on by exaggerated levels of APOBEC3, including changes in splicing pathways. To further investigate the complex relationship between splicing and deaminase deregulation, we treated myeloproliferative neoplasm patient samples and normal HPSCs with Rebecsinib (also known as 17S-FD-895), a pharmacologically stable, potent, and selective small molecule splicing modulator, which interestingly caused significant downregulation of APOBEC3C. We will continue to investigate these findings as a potential target to correct the dysregulation seen in MPN progression. Consequently, we aim to use these findings to identify predictive biomarkers and druggable targets of leukemic initiation progression. Citation Format: Jane Marie Isquith, Jessica Pham, Thomas Whisenant, Larisa Balaian, Catriona Jamieson. Molecular mechanisms of RNA and DNA editing in leukemic transformation of hemopoietic stem and progenitor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 123.
Abstract 2885: RASSF1A133Sresulting from the prevalent SNP rs2073498 is associated with Treg defects
Authors: Haonan Xu, Keaton Jones, Cameron Lang, Simone Lanfredini, Sophie Hughes, Eric O'Neill
Journal: Cancer Research (2023)

Abstract Rs2073498 is a prevalent (~10% population) single nucleotide polymorphism (SNP) that leads to A133S missense mutation in tumor suppressor and Hippo Signaling Pathway scaffold protein RASSF1A. Recent reports have illustrated the crucial involvement of Hippo pathway proteins in lymphocyte recruitment, differentiation, and function. Using a BL/6 mouse model engineered with alanine-to-serine point mutation, we showed that RASSF1A133S is associated with systematic defects in regulatory T cells (Tregs). When blood was phenotyped through a 17-color spectral flow cytometry panel, both RASSF1A133S/WT and RASSF1A133S/A133S carriers had a smaller circulatory CD25+FoxP3+ Treg pool than WT controls. Magnetically sorted splenic T cells were also stimulated with PMA/Ionomycin ex vivo, and fewer Tregs from A133S carriers were expressing anti-inflammatory cytokine IL-10. Preliminary results further demonstrated that RASSF1A133S/WT has fewer intratumor FoxP3+ Tregs in subcutaneously injected MC38 colon adenocarcinoma tumor models. In contrast, A133S did not have any significant effects on thymic T cell maturation states, splenic T cell naïve/memory phenotypes, or Treg survival fitness measured by Fas/FasL and BCL-2 expression. Ex vivo stimulation also demonstrated that A133S carriers retain similar IL-2 sensitivity and phospho-STAT5 response when compared to the controls, although RASSF1 downstream kinases MST1/2 have been reported to amplify IL-2-STAT5 signaling in Tregs (Shi et al., 2018). These results collectively suggest that RASSF1A133S may leads to Treg imbalance and predispose rs2073498 carriers to Treg mediated autoimmune risks. Citation Format: Haonan Xu, Keaton Jones, Cameron Lang, Simone Lanfredini, Sophie Hughes, Eric O'Neill. RASSF1A133Sresulting from the prevalent SNP rs2073498 is associated with Treg defects [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2885.
Abstract 2476: Nischarin is a potential druggable target in both epithelial and stromal compartments of pancreatic ductal adenocarcinoma
Authors: Jelena Grahovac, Kristina Živić, Marijana Pavlović, Marija Ostojić, Ana Đurić, Tatjana Srdić-Rajić, Aleksandar Pavić, Danijel Galun
Journal: Cancer Research (2023)

Abstract Nischarin is a scaffolding protein involved in the regulation of cell cytoskeletal organization and metabolic homeostasis. In breast and ovarian cancers, nischarin has been demonstrated to have tumor suppressive functions. We have found that nischarin was expressed in both the epithelial and stromal compartments of the PDAC patient tissue, in cancer cell lines and patient-derived stellate cells. Of interest, nischarin is a functional imidazoline 1 receptor for which there are several FDA-approved agonists used for treatment of hypertension. The aim of this study was to examine the effects of nischarin agonists on PDAC cancer cells and stellate cells, separately and in co-culture and determine the potential for their repurposing in treatment of PDAC. mRNA sequencing revealed that cancer cell treatment with nischarin agonist rilmenidine induced transcriptional changes associated with regulation of cell adhesion, EMT and vesicular transport. In vitro, rilmenidine treatment of cancer cells decreased their migration and invasion potential and treatment of stellate cells decreased the αSMA-positive fraction. Treatment of cancer cell-stellate cell co-cultures decreased the production of pro-inflammatory cytokines IL-6, IL-8 and CCL-2, known drivers of the metastatic progression. Ultimately, rilmenidine treatment decreased PDAC cell invasion in Tg(fli1: EGFP) zebrafish model. Taken together, nischarin agonist rilmenidine has a potential for limiting the processes involved in PDAC metastatic cascade and may be a good candidate for drug repurposing. Citation Format: Jelena Grahovac, Kristina Živić, Marijana Pavlović, Marija Ostojić, Ana Đurić, Tatjana Srdić-Rajić, Aleksandar Pavić, Danijel Galun. Nischarin is a potential druggable target in both epithelial and stromal compartments of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2476.
Abstract 1999: Repurposing an antibiotic for breast cancer treatment using liposomes as a delivery system
Authors: Janaina Artem Ataide, Nina Filipczak, Satya Siva Kishan Yalamarty, Priscila Gava Mazzola, Vladimir P. Torchilin
Journal: Cancer Research (2023)

Abstract Purpose: Scientific community is always searching for alternatives for cancer treatment and promoting drug repurposing is one of the ways. Rifamycin is a well-known antibiotic, that inhibits RNA synthesis and probably can be explored as cytotoxic agent. Thus, our goal was to repurpose rifamycin for breast cancer treatment using liposomes as a delivery system. Methods: Liposomes were produced by thin-film evaporation method using egg phosphatidylcholine, cholesterol and DOPE-PEG5k (70:25:5, molar ratio). Non-encapsulated drug was removed using dialysis bags and encapsulated drug was directly determined by UV spectrophotometer. Liposomes were characterized regarding size and surface charge by dynamic light scattering. Liposomes were stored at 4°C and 25°C for stability evaluation, monitoring nanoparticles parameters and drug encapsulation. Formulation biocompatibility was evaluated by hemolysis assay. Finally, cytotoxicity of rifamycin SV and liposomes was evaluated in MCF-7 and MDA-MB-231 cell lines. Results: Blank liposomes (without drug) and rifamycin-loaded liposomes showed size smaller than 100 nm and polydispersity around 0.2, with slightly negative zeta potential. Rifamycin encapsulation in liposomes was 3mg of drug/10mg of lipid films. Both formulations were stable for at least 21 days when stored at 4°C, keeping above 60% of drug encapsulated. In the concentrations tested (0.5mg/mL of drug, 2mg/mL of lipids), liposomes formulation (blank and loaded) and free rifamycin were biocompatible and non-hemolytic, since hemolysis was below 6%. Blank liposomes were not cytotoxic in tested cell lines. Free rifamycin and rifamycin-loaded liposomes demonstrated the IC50 in the same range between 41 and 46 µg/mL in 24h and 48h for both MCF-7 and MDA-MB-231. Conclusions: Rifamycin was successfully encapsulated in liposomes, leading to a stable, biocompatible, and non-hemolytic formulation. The liposomal rifamycin demonstrated strong cytotoxicity towards cancer cells similar to that of the free drug. Citation Format: Janaina Artem Ataide, Nina Filipczak, Satya Siva Kishan Yalamarty, Priscila Gava Mazzola, Vladimir P. Torchilin. Repurposing an antibiotic for breast cancer treatment using liposomes as a delivery system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1999.
Abstract 3154: Integrating DNA damage and mutation enrichment to understand mutagenesis at transcription factor binding sites
Authors: Bo Chi, Raluca Gordan
Journal: Cancer Research (2023)

Abstract The buildup of ultraviolet (UV) light-induced DNA damage, such as Cyclobutane Pyrimidine Dimers (CPDs), is a crucial precursor to genetic mutations and the development of skin melanoma. These damaged sites and mutations are known to not be randomly distributed; in fact, previous research suggests potential relationships between damaged/mutated sites and transcription factors (TFs), proteins that regulate gene expression by binding to target sequences across the genome. To examine relationships between UV damages and TF binding sites on a genomic level, we integrated data from the Duke iMADS database of TF binding sites, CPD damage maps across the human genome, ATAC-seq accessibility data from the Cistrome database, and mutation data from Australian melanoma patients (from the ICGC consortium). We developed a computational workflow to measure the spatial distribution of damage/mutations at TF binding sites. Our analysis showed a strong association between the positions of CPD damages and mutations within the binding sites of ETS1, but not E2F or c-Myc, with the peaks in damage/mutations primarily residing at the central core of the ETS1 binding sites. The creation of such an analytic pipeline will enable the further quantitative genome-wide study of the relationships between the degrees of damages/mutations within TF binding sites, chromatin accessibility, and other genomic contexts. With these results, we can better understand the mechanisms involved in accumulating damages and mutations and how they progress to cancer, aging, and senescence. Citation Format: Bo Chi, Raluca Gordan. Integrating DNA damage and mutation enrichment to understand mutagenesis at transcription factor binding sites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3154.
Abstract 4723: DNA G-quadruplex facilitates MYC enhancer-promotor interaction
Authors: Dieila Giomo De Lima, Gustavo Narvaes Guimarães, Bianca Caroline Bianco, Ana Paula De Souza, Aline Cristiane Planello
Journal: Cancer Research (2023)

Abstract Background: G-quadruplexes (G4) are nucleic acid secondary structures formed in guanine-rich regions of DNA or RNA. The biological significance of G4 has been attributed to the regulation of gene expression, and more recently, to the stabilization and generation of enhancer-promotor interaction. Since G4 are enriched in the promoter region of the proto-oncogene MYC, we sought to investigate the role of G4 in stabilizing the enhancer-promoter loop using the locus 8q24 (hg38) 127,700,000-128,500,000 that contains the MYC gene as a model. Methods: Two different cell lines were used, the spontaneously immortalized, non-oncogenic human epidermal keratinocyte (HaCaT), in which the enrichment of G4 in the MYC promoter was demonstrated, and the primary normal human epidermal keratinocyte (nHEK) that is depleted of G4 in MYC promoter. Both cell lines were exposed to the G4 selective stabilizer 360-A drug and the half-maximal inhibitory concentration (IC50) could be calculated. Gene expression was accessed by RT-qPCR and DNA methylation by Methylation-Sensitive High Resolution Melting (MS-HRM). Chromatin Conformation Capture (3C-qPCR) technique was performed interrogating the MYC gene (chr8:127,733,798-127,744,729) and the putative enhancer in the lncRNA PVT1 gene (chr8:127,914,509-127,922,393) to compare the frequency of promoter-enhancer interaction between the two cell lines. Results: The HaCaT cells showed interaction between the MYC promoter and the distal region. The nHEK cells that are not enriched for G4 showed no promoter interaction with the distal region. The use of 360-A in IC50 did not change the results. The gene expression analysis of the MYC showed higher expression in HaCaT cells compared to nHEK. There was no difference in DNA methylation in the MYC promoter between the two cell lines. Conclusions: The data suggest an important role of G4 for the interaction of the MYC promoter and downstream enhancer. Additional analyzes of other genomic regions enriched for G4 should be performed to confirm the mechanism. Citation Format: Dieila Giomo De Lima, Gustavo Narvaes Guimarães, Bianca Caroline Bianco, Ana Paula De Souza, Aline Cristiane Planello. DNA G-quadruplex facilitates MYC enhancer-promotor interaction. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4723.
Abstract 340: Investigating the role of HMGA2 and AR crosstalk in prostate cancer cell proliferation
Authors: Mojisoluwa Simisoluwa Awolowo, Taaliah Campbell, Ohuod Hawsawi, Valerie Odero-Marah
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the most common non-skin cancer in men, and second leading cause of death. PCa occurs when cells within the prostate grow uncontrollably, creating small tumors. Generally, the growth/proliferation of the prostate is regulated by the male hormone, androgen, that binds androgen receptor (AR), a nuclear receptor that functions as a transcription factor and regulates the development and proliferation of the prostate as well as PCa. Interestingly, AR has become one of the leading pathways targets to slow down prostate cancer progression. In fact, enzalutamide a second-generation antiandrogen drug works to inhibit AR translocation into the nucleus. High Mobility Group AT-Hook (HMGA2) is a transcription factor protein that alters the structure of DNA by binding to the promoter region to regulate the transcription of genes. The expression of HMGA2 is associated with cancer proliferation and metastasis and is higher in PCa patients compared to men without cancer. Additionally, this gene has two isoforms HMGA2 full-length/wild-type and truncated (missing the carboxyl terminus). Preliminary studies shown that AR is localized in the nucleus of HMGA2 wild-type but not truncated overexpressing cells. Our hypothesis is that HMGA2 wild-type promotes AR translocation to the nucleus which leads to increased cell proliferation in PCa cells. We utilized HMGA2-wild-type and HMGA2-truncated overexpressing LNCaP cells and C4-2B enzalutamide resistant cells to knockdown either AR or HMGA2 with siRNA followed by western blot analysis, cell proliferation assay, and immunofluorescence. Our results show that HMGA2 siRNA led to decreased expression of wild-type (25 kDa long form) and truncated isoform (17 kDa) protein expression, and cell proliferation when compared to control siRNA. However, AR knockdown decreased AR expression in both cell lines but only decreased cell proliferation in HMGA2-wild-type and C4-2B enzalutamide-resistant cells. This suggests that HMGA2 wild-type works with AR to promote cell proliferation, whereas HMGA2-truncated promotes cell proliferation by an AR-independent mechanism. Therefore, we need to examine how current PCa treatments such as enzalutamide that target AR work in patients expressing differing HMGA2 isoforms. Grant/Other Support: RISE: 5R25GM0058904, NIH/NIMHD 2U54MD007590; 5U54MD013376-8281; NSF S-STEM 2030608. Citation Format: Mojisoluwa Simisoluwa Awolowo, Taaliah Campbell, Ohuod Hawsawi, Valerie Odero-Marah. Investigating the role of HMGA2 and AR crosstalk in prostate cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 340.